This invention relates to novel arginine aldehydes, their salts and hydrates, which compounds selectively exhibit serine proteases inhibitory activity, are highly stable in aqueous solutions, are useful for anti-trypsin and anti-thrombin activity, and to a process for the preparation thereof. 2. Description of the Art
Arginine aldehydes of specific structure are known to inhibit the actions of proteolytic enzymes such as serine, cysteine, trypsin, thrombin, papain and plasmin. Umezawa et al, reported the proteolytic activity of naturally occurring leupeptins. Leupeptins are derivatives of simple tripeptide whose structures have an aldehydic group instead of a carboxyl group in the arginine moiety. (Umezawa et al, Chem Pharm Bull, 17: 1902-1909 (1969)). Recently, McConnell et al, published several analogs of leupeptins which inhibited a number of serine proteases. However, leupeptins are not selective among enzymes of similar substrate specificities, thus limiting their usefulness as therapeutic agents (McConnell, et al, J. Med. Chem., 33:86-93 (1990)).
Thrombin, a key enzyme in the blood coagulation cascade, is involved in the conversion of fibrinogen into fibrin gel during the blood clotting process. U.S. Pat. No. 4,316,889, issued Feb. 25, 1982, U.S. Pat. No. 4,399,065, issued Aug. 16, 1983, and U.S. Pat. No. 4,478,745, issued Oct. 23, 1984 disclose arginine aldehydes derived from amino acids (D-Phe-Pro-Arg-aldehydes) as thrombin inhibitors. However, the recent published data by Bajusz et al, (J. Med. Chem. 33, 1725-35, (1990)) clearly indicate that these aldehydes are not stable in aqueous medium. They undergo a series of intramolecular reactions to produce inactive heterocyclic compounds. See also U.S. Pat. No. 4,703,036, issued Oct. 2, 1987, and J. Med. Chem. 33: 1729-1735, (1990).
Trypsin is secreted by the pancreas in an inactive form, thus preventing autodigestion. Protease inhibitors in the pancreas and pancreatic juice provide protection against autodigestion.
Further disclosed is a process for the preparation of the arginine aldehydes of the present invention.
The present invention discloses novel arginine aldehydes, their salts and hydrates which are stable in aqueous media, selectively inhibit trypsin and thrombin over other serine proteases such as plasmin, and which are useful for anti-trypsin and anti-thrombin activity.